The dominant theoretical form of mental structure of the last century was implicitly a neuropsychological model. At the center of this model, necessary for episodic free recall, planning or logical reasoning, is Hebb's phase sequences of neuronal assemblies, i.e., hypothetical self- propagating loops of neuronal coalitions connected by modifiable synapses. These phase sequences can be activated by exogenous or endogenous (internal) sources of stimulation, allowing the mind a degree of independence from environmental determinants of behavior. The neurophysiological implication of this conjecture for episodic recall is that hippocampal networks are endowed by an internal mechanism that can generate a perpetually changing neuronal activity even in the absence of environmental inputs. Recall of similar episodes would generate similar cell assembly sequences, and uniquely different sequence patterns would reflect different episodes. Recent advances in large-scale recording of neuronal ensembles in the behaving animal have allowed testing this hypothesis. Accordingly, we propose to examine the presence of cell assembly sequences in the hippocampus and entorhinal cortex as a potential substrate of memory recall and/or action planning using a hippocampus-dependent delayed alternation task. To achieve this goal, the experimental animal, rat, will be required to run steadily in a wheel during the delay so that environmental and bodily cues will be kept constant. Our pilot experiments indicate that under these conditions continuously changing cell assemblies form unique sequences specific to the future choice by the rat in the maze. In the first project, traditionally accepted parameters of `place' and `grid' cells during spatial behavior (e.g., `life time' of activity, relation to theta oscillation phase, `temporal compression') will be compared to parameters obtained during wheel running. Experiments in the second project, will examine the conditions (e.g., context, length of experience) that are responsible for establishing the memory specific, unique cell sequence patterns. In the last project, the cell assembly dynamics will be perturbed to examine the causal link between neuronal activity and behavior. The experiments of this proposal will provide an important step towards understanding how emergent, coordinated properties of assembly activity represent cognitive behavior. Dysfunction of self-organized cellular-synaptic mechanisms may underline Alzheimer's disease, schizophrenia and other cognitive diseases. PUBLIC HEALTH RELEVANCE: Using large-scale recording of neuronal activity in the rat, we will examine the hypothesis that self-organized sequences of neuronal assemblies in the hippocampus underlie memory recall and/or planning. Similar internally generated cell assembly sequences may be responsible for several other cognitive functions, including planning and logical reasoning. Dysfunction of self-organized cellular-synaptic mechanisms may underline Alzheimer's disease, schizophrenia and other cognitive diseases.